PROJECT SUMMARY/ABSTRACT Experiencing the death of a loved one is inevitable, and grief is a natural response. Most older adults are resilient and recover their pre-loss functioning within one year. However, in a significant minority, acute grief (AG) becomes unusually protracted, intense, and debilitating, resulting in complicated or prolonged grief (CG), a unique and recognizable condition. The public health consequences of CG are enormous, and include negative medical, cognitive, and cognitive health outcomes, and an increased risk of suicide. Despite the magnitude of this problem, we cannot distinguish those who are resilient and will successfully transition to integrated grief within one year from those who are prone to CG trajectories. Neurobiological markers that can characterize the clinical course for those experiencing AG following a major loss are critically needed. Such biomarkers that would, in the future, aid the predictive validity of the construct of CG have not been identified. The emotion regulation (ER) theory has been used to explain the neurobiological underpinnings of grief and related symptoms. Accordingly, an intact ER neural system could play an important role in coping with grief, separation distress including sadness, and eventual acceptance of the loss. Our central hypothesis is that, in older adults with AG, brain network function features of emotion dysregulation are early and critical measures of heterogeneous grief trajectories and persistence of CG symptoms. Specifically, we theorize that amygdala hyperactivity and enhanced amygdala-frontal functional connectivity relates to worsening complicated grief symptom trajectories in older individuals with acute grief. To achieve our objective, a total of 170 older adults (>60 years of age) will be enrolled into the following groups that are equated for age and gender: (1) AG (n=115) and (2) healthy comparison (HC) (n=55) subjects. This study employs a longitudinal design wherein the following aims will be completed: Aim 1. To determine the ER brain network function features of acute grief. Extensive clinical and neuroimaging assessments will be conducted at baseline in AG and HC participants. Aim 2. To characterize the clinical trajectories using baseline ER brain network function features in AG. The AG and HC participants from Aim 1 will be followed longitudinally for one year with serial clinical assessments to evaluate multidimensional symptom trajectories and identify those with CG at one year. Aim 3. To explore the relationships between ER brain network changes and clinical trajectories. AG and HC participants will complete a second brain MRI to quantify ER brain network function measures at one year. We expect to identify brain network function biomarkers of emotion dysregulation that, in the future, could serve as predictors of pathological grief symptom trajectories and CG persistence in older adults following bereavement. In the future, these biomarkers could also serve as novel targets for treatment or prevention strategies in older AG subjects at risk for a maladaptive grief response and CG development.